Influenza A viruses of the H2, H3, and H6 subtypes function as T cell-independent B cell mitogens for lymphocytes from BALB/c mice. Lymphocytes from C57BL/10 mice, however, undergo mitogenesis only in response to H3 viruses. The failure of C57BL/10 lymphocytes to respond to H2 and H6 viruses was shown not to reflect a difference in dose-response profile or kinetics of the response, nor was it due to the activity of suppressor T cells. Experiments with congenic and recombinant strains of mice established that mitogenic responsiveness to H2 and H6 viruses is linked to the major histocompatibility complex, and is controlled by a gene located in the I-E/C subregion. Furthermore, responsiveness was shown to correlate with the expression of surface I-E antigen, being positive for mouse strains that express I-E antigen (haplotypes a, d, k, p, r) and negative for strains that do not (haplotypes b, f, q, s). The data suggest that influenza A viruses of the H2 and H6 subtypes may interact directly with I-E molecules on the surface of B cells or possibly on an accessory cell. Because mitogenesis by H3 viruses is not I-E dependent, it appears that influenza A viruses stimulate B cell mitogenesis by at least two different mechanisms.